Asymmetric Activation Research Articles

The mechanism of MinD stability modulation by MinE in Min protein dynamics.

The patterns formed both in vivo and in vitro by the Min protein system have attracted much interest because of the complexity of their dynamic interactions given the apparent simplicity of the component parts. Despite both the experimental and theoretical attention paid to this system, the details of the biochemical interactions of MinD and MinE, the proteins responsible for the patterning, are still unclear. For example, no model consistent with the known biochemistry has yet accounted for the observed dual role of MinE in the membrane stability of MinD. Until now, a statistical comparison of models to the time course of Min protein concentrations on the membrane has not been carried out. Such an approach is a powerful way to test existing and novel models that are difficult to test using a purely experimental approach. Here, we extract time series from previously published fluorescence microscopy time lapse images of in vitro experiments and fit two previously described and one novel mathematical model to the data. We find that the novel model, which we call the Asymmetric Activation with Bridged Stability Model, fits the time-course data best. It is also consistent with known biochemistry and explains the dual MinE role via MinE-dependent membrane stability that transitions under the influence of rising MinE to membrane instability with positive feedback. Our results reveal a more complex network of interactions between MinD and MinE underlying Min-system dynamics than previously considered.

Variability analysis of muscle activation symmetry to identify indicators of individual motor strategy: a case series on elite Paralympic powerlifters.

In Paralympic powerlifting competitions, movement execution symmetry is a technical requirement influenced by individual athlete characteristics and motor strategies. Identifying the elements associated with individual motor strategies can offer valuable insight for improving sport performance. Therefore, this case series study aimed to explore muscle activation symmetry and its intra- and inter-individual variability to determine the muscles mostly related to individual motor strategies in elite Paralympic powerlifters. Bilateral electromyographic activation of the anterior deltoid (AD), pectoralis major (PM), latissimus dorsi (LD), triceps (TRI) and external oblique (EO) muscles were analysed in five elite Paralympic powerlifters while performing four sets of one-repetition maximum of Paralympic bench press. Muscle activation symmetry indexes (SI) were obtained and transformed to consider individual-independent evaluation. The coefficient of variation (CV), variance ratio (VR), and mean deviation (MD) were computed to assess inter- and intra-individual variability in electromyographic waveforms and SI. Both transformed and non-transformed SI indicated overall symmetric activation in DA, PM, TRI, and LD. Transformed SI revealed asymmetrical muscle activation of EO when grouping data (mean bilateral difference: 10%). Athletes exhibited low intra-individual SI variability in all analysed muscles (CV < 10%) and low inter-individual variability in DA, PM, LD, and TRI (CV < 10%; VR: 4%-11%; MD: 29%-43%). In contrast, higher inter-individual variability was observed in EO (CV: 23%; VR: 23%; MD: 72%-81%). The highest variability and asymmetry in abdominal muscle activation among athletes emphasize the importance of personalized training approaches for targeting these muscles due to their role in individualizing motor strategies.

Experimental protocol to investigate cortical, muscular and body representation alterations in adolescents with idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is the most common form of scoliosis. AIS is a three-dimensional morphological spinal deformity that affects approximately 1-3% of adolescents. Not all factors related to the etiology of AIS have yet been identified. The primary aim of this experimental protocol is to quantitatively investigate alterations in body representation in AIS, and to quantitatively and objectively track the changes in body sensorimotor representation due to treatment. Adolescent girls with a confirmed diagnosis of mild (Cobb angle: 10°-20°) or moderate (21°-35°) scoliosis as well as age and sex-matched controls will be recruited. Participants will be asked to perform a 6-min upright standing and two tasks-named target reaching and forearm bisection task. Eventually, subjects will fill in a self-report questionnaire and a computer-based test to assess body image. This evaluation will be repeated after 6 and 12 months of treatment (i.e., partial or full-time brace and physiotherapy corrective postural exercises). We expect that theta brain rhythm in the central brain areas, alpha brain rhythm lateralization and body representation will change over time depending on treatment and scoliosis progression as a compensatory strategy to overcome a sensorimotor dysfunction. We also expect asymmetric activation of the trunk muscle during reaching tasks and decreased postural stability in AIS. Quantitatively assess the body representation at different time points during AIS treatment may provide new insights on the pathophysiology and etiology of scoliosis.

Asymmetric gating of a human hetero-pentameric glycine receptor

Hetero-pentameric Cys-loop receptors constitute a major type of neurotransmitter receptors that enable signal transmission and processing in the nervous system. Despite intense investigations into their working mechanism and pharmaceutical potentials, how neurotransmitters activate these receptors remains unclear due to the lack of high-resolution structural information in the activated open state. Here we report near-atomic resolution structures resolved in digitonin consistent with all principle functional states of the human α1β GlyR, which is a major Cys-loop receptor that mediates inhibitory neurotransmission in the central nervous system of adults. Glycine binding induces cooperative and symmetric structural rearrangements in the neurotransmitter-binding extracellular domain but asymmetrical pore dilation in the transmembrane domain. Symmetric response in the extracellular domain is consistent with electrophysiological data showing cooperative glycine activation and contribution from both α1 and β subunits. A set of functionally essential but differentially charged amino acid residues in the transmembrane domain of the α1 and β subunits explains asymmetric activation. These findings provide a foundation for understanding how the gating of the Cys-loop receptor family members diverges to accommodate specific physiological environments.

A Simple Screening and Optimization Bioprocess for Long-Chain Peptide Catalysts Applied to Asymmetric Aldol Reaction.

Peptides have demonstrated their efficacy as catalysts in asymmetric aldol reactions. But the constraints inherent in chemical synthesis have imposed limitations on the viability of long-chain peptide catalysts. A noticeable dearth of tools has impeded the swift and effective screening of peptide catalysts using biological methods. To address this, we introduce a straightforward bioprocess for the screening of peptide catalysts for asymmetric aldol reactions. We synthesized several peptides through this method and obtained a 15-amino acid peptide. This peptide exhibited asymmetric aldol catalytic activity, achieving 77% ee in DMSO solvent and 63% ee with over an 80.8% yield in DMSO mixed with a pH 9.0 buffer solution. The successful application of our innovative approach not only represents an advancement but also paves the way for currently unexplored research avenues.

UBR-1 ubiquitin ligase regulates the balance between GABAergic and glutamatergic signaling.

Excitation/inhibition (E/I) balance is carefully maintained by the nervous system. The neurotransmitter GABA has been reported to be co-released with its sole precursor, the neurotransmitter glutamate. The genetic and circuitry mechanisms to establish the balance between GABAergic and glutamatergic signaling have not been fully elucidated. Caenorhabditis elegans DVB is an excitatory GABAergic motoneuron that drives the expulsion step in the defecation motor program. We show here that in addition to UNC-47, the vesicular GABA transporter, DVB also expresses EAT-4, a vesicular glutamate transporter. UBR-1, a conserved ubiquitin ligase, regulates DVB activity by suppressing a bidirectional inhibitory glutamate signaling. Loss of UBR-1 impairs DVB Ca2+ activity and expulsion frequency. These impairments are fully compensated by the knockdown of EAT-4 in DVB. Further, glutamate-gated chloride channels GLC-3 and GLC-2/4 receive DVB's glutamate signals to inhibit DVB and enteric muscle activity, respectively. These results implicate an intrinsic cellular mechanism that promotes the inherent asymmetric neural activity. We propose that elevated glutamate in ubr-1 mutants, being the cause of the E/I shift, potentially contributes to Johanson Blizzard syndrome.

Asymmetric Activation of Frontal Brain Regions during Cognitive Reappraisal Generation—A Function of Implemented Reappraisal Strategy?

Prefrontal cortex activity facilitates emotion regulation by cognitive reappraisal. Yet, neuroimaging studies have yielded disparate findings as to whether relatively greater left or right prefrontal activity is more beneficial for reappraisal success. We argue that differences in hemispheric activation during reappraisal efforts may depend on the specific and diverse cognitive strategies utilized to reappraise negative stimuli. In this EEG study, n = 94 participants were randomly assigned to three groups and instructed to either generate problem-oriented reappraisals, positive reinterpretations, or distancing reappraisals for anger-eliciting situations while EEG alpha asymmetry changes in the prefrontal cortex were recorded (F3–F4, F7–F8, and Fp1–Fp2). Engaging in problem orientation yielded a right-lateralized frontal activation pattern and was linked to the highest reappraisal success (percentage of strategy-conforming reappraisals), along with the highest believability ratings. Conversely, engaging in distancing reappraisal yielded a left-lateralized frontal EEG pattern, along with the highest ideational fluency and lowest anger ratings post-reappraisal. No distinct asymmetry pattern emerged for positive reinterpretation; however, this reappraisal condition yielded the lowest reappraisal success and lowest believability ratings. For all groups, higher reappraisal capacity correlated with right-lateralized frontal activity. Frontal EEG alpha asymmetry observed during reappraisal may be a specific function of implemented reappraisal strategy rather than general ideational fluency.

Hybridization led to a rewired pluripotency network in the allotetraploid Xenopus laevis.

After fertilization, maternally contributed factors to the egg initiate the transition to pluripotency to give rise to embryonic stem cells, in large part by activating de novo transcription from the embryonic genome. Diverse mechanisms coordinate this transition across animals, suggesting that pervasive regulatory remodeling has shaped the earliest stages of development. Here, we show that maternal homologs of mammalian pluripotency reprogramming factors OCT4 and SOX2 divergently activate the two subgenomes of Xenopus laevis, an allotetraploid that arose from hybridization of two diploid species ~18 million years ago. Although most genes have been retained as two homeologous copies, we find that a majority of them undergo asymmetric activation in the early embryo. Chromatin accessibility profiling and CUT&RUN for modified histones and transcription factor binding reveal extensive differences in predicted enhancer architecture between the subgenomes, which likely arose through genomic disruptions as a consequence of allotetraploidy. However, comparison with diploid X. tropicalis and zebrafish shows broad conservation of embryonic gene expression levels when divergent homeolog contributions are combined, implying strong selection to maintain dosage in the core vertebrate pluripotency transcriptional program, amid genomic instability following hybridization.

Balance of peripheral input and integrity of the electrode-nerve interface in a large cohort of children with bilateral cochlear implants

The study aim was to determine whether asymmetries in the electrode-nerve interface were present in children using bilateral cochlear implants (CIs). Bilateral CIs improve hearing over unilateral CIs in children with profound deafness in both ears but benefits decrease with increasing asymmetric activity and function between ears. Effects of asymmetry between bilateral CI arrays, CI stimulation parameters, impedance and transimpedance measurements, and electrophysiological thresholds could exacerbate asymmetries at the electrode-nerve interface but these factors have not been assessed in children using bilateral CIs. Clinically generated data from a large cohort of Canadian children (n = 669 children, n = 1332 devices) was gathered retrospectively for analyses. To account for repeated measures, a mixed effects modeling analysis was conducted. Despite CI electrical stimulation levels and electrophysiological thresholds being largely stable over time, asymmetries based on implantation sequence were observed. The observed bilateral differences suggest spread of current and sensitivity to electrical stimulation vary between devices in the same individual. These peripheral asymmetries may coincide with previously reported plasticity-induced cortical changes to increase asymmetries in auditory function between ears and restrict access to binaural hearing cues.

Functional Asymmetry During Working Memory and Its Association with Markers of Alzheimer's Disease in Cognitively Normal Older Adults.

Amyloid-β (Aβ) deposits asymmetrically early in Alzheimer's disease (AD). This process is variable and has been associated with asymmetric hypometabolism. We investigated whether neural asymmetry during working memory and executive function processing was associated with AD genetic risk and markers of AD as well as other brain neuropathology biomarkers, cognitive function, and cognitive reserve in cognitively normal older adults. We analyzed data from 77 cognitively healthy, older adults who completed functional magnetic resonance imaging, positron emission tomography, and cognitive testing. We identified regions of significant activation and asymmetry during the Digital Symbol Substitution Task (DSST). We examined associations between regions with significant hemispheric asymmetry (directional and absolute) and global cerebral Aβ, cerebral glucose metabolism, white matter hyperintensities, APOE ɛ4 allele status, DSST reaction time, age, sex, education, and cognitive function. Asymmetry was not associated with several factors including cognitive function, Aβ, and white matter hyperintensities. The presence of at least one ɛ4 APOE allele in participants was associated with less asymmetric activation in the angular gyrus (right dominant activation). Greater education was associated with less asymmetric activation in mediodorsal thalamus (left dominant activation). Genetic risk of AD was associated with lower asymmetry in angular gyrus activation, while greater education was associated with lower asymmetry in mediodorsal thalamus activation. Changes in asymmetry may reflect components of compensation or cognitive reserve. Asymmetric neural recruitment during working memory may be related to maintenance of cognitive function in cognitively normal older adults.

A revised model for activity–composition relations in solid and molten FePt alloys and a preliminary model for characterization of oxygen fugacity in high-pressure experiments

Abstract. We present new models for the activity of iron (γFe) in solid face-centered cubic (fcc) and liquid FePt alloy at high temperature and pressure to facilitate their use as sliding buffer redox sensors under extreme conditions. Numerous experimental studies of γFe in FePt alloy at 100 kPa have produced a wide spread of values. By favoring high-temperature studies that are more likely to have produced equilibrium measurement and excluding experiments for compositions and temperatures that probably encountered ordered or unmixed low-temperature phases, we regress an asymmetric Margules activity–composition model with parameters WFePtfcc=-121.5±2.1 kJ mol−1 and WPtFefcc=-93.3±4.3 kJ mol−1. These values are close to the widely used model of Kessel et al. (2001), but for Pt-rich compositions they predict larger Fe activities and correspondingly more reduced oxygen fugacities. Activity–composition relations in liquid FePt are calibrated from direct measurements of activities and, most sensitively, from the trace of the Fe–Pt liquidus. Together, these yield asymmetric Margules parameters of WFePtliq=-124.5 kJ mol−1 and WPtFeliq=-94.0 kJ mol−1. The effects of pressure on both fcc and liquid FePt alloy are considered from excess-volume relations. Both solid and liquid alloy display significant positive excess volumes of mixing. Extraction of the excess volume of mixing for fcc FePt alloy requires filtering data for ordered low-temperature phases and corrections for the effects of magnetostriction on Fe-rich compositions which exhibit “Invar” behavior. Applied at high temperatures and pressures, both solid and liquid FePt alloys have strongly negative deviations from ideality at low pressure, which become closer to ideal at high pressure. These models provide a provisional basis for the calculation of aFe in high-temperature, high-pressure experiments that, when combined with estimates of aFeO, allow characterization of fO2 under conditions relevant to magma oceans, core formation, and differentiation processes in the lower mantle of Earth or on other terrestrial planets. Improvements in these models require new constraints on the equation of state of FePt fcc alloy and documentation of the high-pressure melting relations in the system Fe–Pt.

Deciphering the Morphological Origins of X-shaped Radio Galaxies: Numerical Modeling of Backflow versus Jet Reorientation

X-shaped radio galaxies (XRGs) develop when certain extragalactic jets deviate from their propagation path. An asymmetric ambient medium (backflow model) or complex active galactic nucleus activity (jet-reorientation model) enforcing the jet direction to deviate may cause these structures. In this context, the present investigation focuses on the modeling of XRGs by performing 3D relativistic magnetohydrodynamic simulations. We implement different jet-propagation models applying an initially identical jet-ambient medium configuration to understand distinctive features. This study, the first of its kind, demonstrates that all adopted models produce XRGs with notable properties, thereby challenging the notion of a universal model. Jet reorientation naturally explains several contentious properties of XRGs, including wing alignment along the ambient medium’s primary axis, development of collimated lobes, and the formation of noticeably longer wings than active lobes. These XRGs disrupt the cluster medium by generating isotropic shocks and channeling more energy than in the backflow scenario. Our synthetic thermal X-ray maps of the cluster medium reveal four clear elongated cavities associated with the wing-lobe alignment, regardless of projection effects, but they affect their age estimation. We show that the depth and geometric alignment of the evolved cavities may qualify as promising characteristics of XRGs, which may be used to disentangle different formation scenarios.

Asymmetric catalysis within chiral zeolitic nanospaces: Chiral host-guest match in GTM-3 zeolite

In this work, the asymmetric catalytic activity of the recently discovered GTM-3 chiral zeolite is systematically explored for the ring-opening of trans-stilbene oxide using alcohols of different size as nucleophiles. Catalytic results show a volcano-type curve with a clear maximum enantioselective activity for a specific linear alcohol size of 4C (1-butanol); this is perfectly reproduced in opposite sign for GTM-3 catalysts obtained with the antipode of the structure-directing agent. Such trend evidences that a proper chiral host-guest size match must be established between the reactants and/or transition states and the chiral confined space provided by the zeolite framework in order for the zeolite catalyst to manifest its chirality. Moreover, secondary alcohols, bulkier in size, give higher enantioselectivities than their linear counterparts. On the other hand, variation of the reaction conditions enables to maximize the enantioselectivity of the reaction: in particular, variation of the concentration of the epoxide displays a strong influence, notably improving the enantiomeric excess obtained when the concentration of the epoxide is reduced. Modification of the reaction temperature also influences the enantiomeric excess, and especially, the selectivity to the different products. Our results suggest that if a proper chiral host-guest match is established within the confined chiral nanospace of the zeolite framework, then the enantioselectivity as well as the selectivity to the chiral products is maximized, which indeed can be manipulated through variations of the reaction conditions, leading to unprecedented enantiomeric excess values up to 51%.

N-methyl acetamide asymmetric vibrational activation

N-methyl acetamide asymmetric vibrational activation

Axially Chiral Borinic Acid Catalysts: Design, Synthesis, and Application in Alkylative Desymmetrization of 1,2-Diols.

A novel chiral borinic acid (CBA), an organocatalyst possessing a binaphthyl skeleton, was designed and synthesized. The synthesis of CBA was achieved with a 72% yield in four steps starting with optically pure 1,1'-bi-2-naphthol. The asymmetric catalytic activity was investigated in the desymmetrization of meso-1,2-diol.

Time space and single-cell resolved tissue lineage trajectories and laterality of body plan at gastrulation

Understanding of the molecular drivers of lineage diversification and tissue patterning during primary germ layer development requires in-depth knowledge of the dynamic molecular trajectories of cell lineages across a series of developmental stages of gastrulation. Through computational modeling, we constructed at single-cell resolution, a spatio-temporal transcriptome of cell populations in the germ-layers of gastrula-stage mouse embryos. This molecular atlas enables the inference of molecular network activity underpinning the specification and differentiation of the germ-layer tissue lineages. Heterogeneity analysis of cellular composition at defined positions in the epiblast revealed progressive diversification of cell types. The single-cell transcriptome revealed an enhanced BMP signaling activity in the right-side mesoderm of late-gastrulation embryo. Perturbation of asymmetric BMP signaling activity at late gastrulation led to randomization of left-right molecular asymmetry in the lateral mesoderm of early-somite-stage embryo. These findings indicate the asymmetric BMP activity during gastrulation may be critical for the symmetry breaking process.

Asymmetry of individual activity promotes cooperation in the spatial prisoner's dilemma game.

We consider an aspiration-based asymmetric individual activity co-evolutionary prisoner's dilemma game model on the square lattice. In detail, each player has an individual weight that evolves with its strategy. We introduce an asymmetric setting that only μ fractions of players in the network chosen to be active can update their individual weights according to whether their payoffs satisfy their aspirations. Therefore, our individual weights can be regarded as a type of intrinsic motivation satisfaction. Through Monte Carlo simulations on the square lattice, our co-evolution mechanism has been proven to significantly promote cooperation. Furthermore, we find that the moderate μ leads to the highest cooperation level. By dividing the players into four types according to their strategies and weights, we prove that the inversion of the dominant relationship between cooperators and defectors with low weights leads to a conversion cycle of the four types of players, which enhances spatial reciprocity to promote cooperation. Moderate μ results in an appropriate number of low-weight players in this cycle. Interestingly, our results show that higher weight heterogeneity does not lead to higher levels of cooperation, which is contrary to the intuition formed in the previous work.

The minus-end depolymerase KIF2A drives flux-like treadmilling of γTuRC-uncapped microtubules.

During mitosis, microtubules in the spindle turn over continuously. At spindle poles, where microtubule minus ends are concentrated, microtubule nucleation and depolymerization, the latter required for poleward microtubule flux, happen side by side. How these seemingly antagonistic processes of nucleation and depolymerization are coordinated is not understood. Here, we reconstitute this coordination in vitro combining different pole-localized activities. We find that the spindle pole-localized kinesin-13 KIF2A is a microtubule minus-end depolymerase, in contrast to its paralog MCAK. Due to its asymmetric activity, KIF2A still allows microtubule nucleation from the γ-tubulin ring complex (γTuRC), which serves as a protective cap shielding the minus end against KIF2A binding. Efficient γTuRC uncapping requires the combined action of KIF2A and a microtubule severing enzyme, leading to treadmilling of the uncapped microtubule driven by KIF2A. Together, these results provide insight into the molecular mechanisms by which a minimal protein module coordinates microtubule nucleation and depolymerization at spindle poles consistent with their role in poleward microtubule flux.

Asymmetric Dual Enamine Catalysis/Hydrogen Bonding Activation

Asymmetric enamine base activation of carbonyl compounds is a well-known and widely used strategy for providing functionalization of organic compounds in an efficient way. The use of solely organic substances, which in most cases are commercially available primary or secondary amines that are easy to obtain, avoids the use of hazardous substances or metal traces, making this type of catalysis a highly convenient methodology from a sustainable point of view. In many cases, the reactivity or the stereoselectivity obtained is far from being a practical and advantageous strategy; this can be improved by using a hydrogen bonding co-catalyst that can help during the activation of one species or by using a bifunctional catalyst that can direct the approximation of reagents during the reaction outcome. In this review, we describe the most efficient methodologies that make use of a dual activation of reagents for performing α-functionalization (enamine activation) or remote functionalization (such as dienamine or trienamine activation) of carbonyl compounds.

The effect of HD-tDCS on brain oscillations and frontal synchronicity during resting-state EEG in violent offenders with a substance dependence.

Violence is a major problem in our society and therefore research into the neural underpinnings of aggression has grown exponentially. Although in the past decade the biological underpinnings of aggressive behavior have been examined, research on neural oscillations in violent offenders during resting-state electroencephalography (rsEEG) remains scarce. In this study we aimed to investigate the effect of high-definition transcranial direct current stimulation (HD-tDCS) on frontal theta, alpha and beta frequency power, asymmetrical frontal activity, and frontal synchronicity in violent offenders. Fifty male violent forensic patients diagnosed with a substance dependence were included in a double-blind sham-controlled randomized study. The patients received 20 minutes of HD-tDCS two times a day on five consecutive days. Before and after the intervention, the patients underwent a rsEEG task. Results showed no effect of HD-tDCS on the power in the different frequency bands. Also, no increase in asymmetrical activity was found. However, we found increased synchronicity in frontal regions in the alpha and beta frequency bands indicating enhanced connectivity in frontal brain regions as a result of the HD-tDCS-intervention. This study has enhanced our understanding of the neural underpinnings of aggression and violence, pointing to the importance of alpha and beta frequency bands and their connectivity in frontal brain regions. Although future studies should further investigate the complex neural underpinnings of aggression in different populations and using whole-brain connectivity, it can be suggested with caution, that HD-tDCS could be an innovative method to regain frontal synchronicity in neurorehabilitation.